Fig. 4.

Insulin signalling regulates the activity of FOXO and NRF2. The role of insulin signalling is primarily the maintenance of glucose homeostasis and anabolic processes. GSK3β is an enzyme that counteracts insulin-stimulated glycogen formation. In addition, GSK3β inhibits NRF2 via phosphorylation and nuclear exclusion, thus impacting the generation of reducing equivalents (e.g. NADPH) necessary for anabolic reactions. However, phosphorylated (i.e. active) AKT2 leads to inhibitory phosphorylation of GSK3β, therefore leaving NRF2 active. In contrast, AKT2 also phosphorylates and inhibits FOXO, a major transcription factor regulating cellular responses to fasting.